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Androgens – Free Register to Access Experts & Abstracts

Colleen C Nelson – One of the best experts on this subject based on the ideXlab platform.

  • androgen levels increase by intratumoral de novo steroidogenesis during progression of castration resistant prostate cancer
    Cancer Research, 2008
    Co-Authors: Jennifer A Locke, Emma S Guns, Amy A Lubik, Hans Adomat, Stephen C Hendy, Catherine A Wood, Susan Ettinger, Martin E Gleave, Colleen C Nelson

    Abstract:

    Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum Androgens. Recent evidence indicates that intraprostatic levels of Androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by Androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that Androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor Androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [(14)C]acetic acid to dihydrotestosterone and uptake of [(3)H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration.

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  • androgen levels increase by intratumoral de novo steroidogenesis during progression of castration resistant prostate cancer
    Cancer Research, 2008
    Co-Authors: Jennifer A Locke, Emma S Guns, Amy A Lubik, Hans Adomat, Stephen C Hendy, Catherine A Wood, Susan Ettinger, Martin E Gleave, Colleen C Nelson

    Abstract:

    Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum Androgens. Recent evidence indicates that intraprostatic levels of Androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by Androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that Androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor Androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [ 14 C]acetic acid to dihydrotestosterone and uptake of [ 3 H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration. [Cancer Res 2008;68(15):6407–15]

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  • differential regulation of clusterin and its isoforms by Androgens in prostate cells
    Journal of Biological Chemistry, 2007
    Co-Authors: Dawn R Cochrane, Zhou Wang, Martin E Gleave, Motosugu Muramaki, Colleen C Nelson

    Abstract:

    Clusterin mRNA levels were shown to increase dramatically in rat ventral prostate following castration, and clusterin was therefore originally thought to be repressed by Androgens. It was later discovered that the increased clusterin levels are most likely due to castration-induced apoptosis of the prostatic epithelium rather than direct action of the androgen receptor (AR). In the studies presented here, LNCaP cells in culture and rat prostate organ culture were treated with Androgens. Clusterin mRNA and protein are shown to increase with androgen treatment in a time- and dose-dependent manner. This induction of clusterin requires AR and can be inhibited by casodex, an AR antagonist. We have found that the first intron of the clusterin gene contains putative androgen response elements. The intronic region is shown to be bound by AR in chromatin immunoprecipitation assays and is transactivated by AR in reporter assays. Two isoforms of clusterin result from alternate transcriptional start sites. Both isoforms are cytoprotective; however, Isoform 1 has the capacity to produce a splice variant that is apoptotic. Real time PCR was used to determine the response of the two isoforms to Androgens. Intriguingly, these results illustrated that Isoform 2 was up-regulated, whereas Isoform 1 was down-regulated by Androgens. Isoform 2 was also increased as the LNCaP xenograft tumor progressed to androgen-independence, whereas Isoform 1 was unaltered. This androgen regulation of clusterin may underline the cytoprotective role of Androgens in normal prostate physiology as well as play an antiapoptotic role in prostate cancer progression.

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Martin E Gleave – One of the best experts on this subject based on the ideXlab platform.

  • androgen levels increase by intratumoral de novo steroidogenesis during progression of castration resistant prostate cancer
    Cancer Research, 2008
    Co-Authors: Jennifer A Locke, Emma S Guns, Amy A Lubik, Hans Adomat, Stephen C Hendy, Catherine A Wood, Susan Ettinger, Martin E Gleave, Colleen C Nelson

    Abstract:

    Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum Androgens. Recent evidence indicates that intraprostatic levels of Androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by Androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that Androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor Androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [(14)C]acetic acid to dihydrotestosterone and uptake of [(3)H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration.

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  • androgen levels increase by intratumoral de novo steroidogenesis during progression of castration resistant prostate cancer
    Cancer Research, 2008
    Co-Authors: Jennifer A Locke, Emma S Guns, Amy A Lubik, Hans Adomat, Stephen C Hendy, Catherine A Wood, Susan Ettinger, Martin E Gleave, Colleen C Nelson

    Abstract:

    Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum Androgens. Recent evidence indicates that intraprostatic levels of Androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by Androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that Androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor Androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [ 14 C]acetic acid to dihydrotestosterone and uptake of [ 3 H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration. [Cancer Res 2008;68(15):6407–15]

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  • differential regulation of clusterin and its isoforms by Androgens in prostate cells
    Journal of Biological Chemistry, 2007
    Co-Authors: Dawn R Cochrane, Zhou Wang, Martin E Gleave, Motosugu Muramaki, Colleen C Nelson

    Abstract:

    Clusterin mRNA levels were shown to increase dramatically in rat ventral prostate following castration, and clusterin was therefore originally thought to be repressed by Androgens. It was later discovered that the increased clusterin levels are most likely due to castration-induced apoptosis of the prostatic epithelium rather than direct action of the androgen receptor (AR). In the studies presented here, LNCaP cells in culture and rat prostate organ culture were treated with Androgens. Clusterin mRNA and protein are shown to increase with androgen treatment in a time- and dose-dependent manner. This induction of clusterin requires AR and can be inhibited by casodex, an AR antagonist. We have found that the first intron of the clusterin gene contains putative androgen response elements. The intronic region is shown to be bound by AR in chromatin immunoprecipitation assays and is transactivated by AR in reporter assays. Two isoforms of clusterin result from alternate transcriptional start sites. Both isoforms are cytoprotective; however, Isoform 1 has the capacity to produce a splice variant that is apoptotic. Real time PCR was used to determine the response of the two isoforms to Androgens. Intriguingly, these results illustrated that Isoform 2 was up-regulated, whereas Isoform 1 was down-regulated by Androgens. Isoform 2 was also increased as the LNCaP xenograft tumor progressed to androgen-independence, whereas Isoform 1 was unaltered. This androgen regulation of clusterin may underline the cytoprotective role of Androgens in normal prostate physiology as well as play an antiapoptotic role in prostate cancer progression.

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V A Randall – One of the best experts on this subject based on the ideXlab platform.

  • balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non balding scalp
    Journal of Endocrinology, 1998
    Co-Authors: Nigel A. Hibberts, A E Howell, V A Randall

    Abstract:

    Androgens can gradually transform large scalp hair follicles to smaller vellus ones, causing balding. The mechanisms involved are unclear, although Androgens are believed to act on the epithelial hair follicle via the mesenchymederived dermal papilla. This study investigates whether the levels and type of androgen receptors in primary lines of cultured dermal papilla cells derived from balding scalp hair follicles diVer from those of follicles from non-balding scalp. Androgen receptor content was measured by saturation analysis using the non-metabolisable androgen, [ 3 H]mibolerone (0·05‐10 nM) in a 9‐10 point assay. Pubic dermal fibroblasts and Shionogi cells were examined as positive controls. Repetitive assays of Shionogi cells showed good precision in the levels of androgen receptor content (coeYcient of variation=3·7%). Specific, high aYnity, low capacity androgen receptors were detected in dermal papilla cells from both balding and non-balding follicles. Balding cells contained significantly (P<0·01) greater levels of androgen receptors (Bmax=0·06&0·01 fmol/10 4 cells (mean&s.e.m.)) than those from non-balding scalp (0·04&0·001). Competition studies with a range of steroids showed no diVerences in receptor binding specificity in the two cell types. The higher levels of androgen receptors in cells from balding scalp hair follicles with similar properties to those from non-balding scalp concur with the expectations from their in vivo responses to Androgens. This supports the hypothesis that Androgens act via the dermal papilla and suggests that cultured dermal papilla cells may oVer a model system for studying androgen action in androgenetic alopecia.

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  • Mechanism of androgen action in cultured dermal papilla cells derived from human hair follicles with varying responses to Androgens in vivo.
    The Journal of investigative dermatology, 1992
    Co-Authors: V A Randall, M J Thornton, K. Hamada, Andrew G. Messenger

    Abstract:

    Androgens are major regulators of human hair growth, but their effects vary: many follicles are stimulated by Androgens, e.g., beard; some remain unaffected, e.g., eyelashes; whereas scalp follicles undergo regression and balding in genetically disposed individuals. Because the dermal papilla controls many aspects of the hair follicle, Androgens may act via the dermal papilla, affecting the other follicular components indirectly. In this hypothesis Androgens would alter dermal papilla cell production of regulatory substances, e.g., growth factors and/or extracellular matrix components. To test this theory the mechanism of androgen action has been compared in primary lines of dermal papilla cells cultured from androgen-dependent follicles and relatively androgen-independent non-balding scalp. Androgen receptor levels were assayed by saturation analysis (9-10 points; 0.05-10 nmol/l) using the synthetic androgen [3H]-mibolerone and specificity was confirmed by competition studies. Androgen metabolism was investigated both intracellularly and in the media after a 2-h incubation with 5 nM [3H]-testosterone. Carrier and [14C] steroids were added to the extracts before separation by thin-layer chromatography; steroid identity was confirmed by recrystallization. Dermal papilla cells from androgen-dependent follicles contained higher levels of specific, high-affinity, low-capacity androgen receptors than non-balding scalp cells. Testosterone metabolism also varied with beard, public and scalp cells containing testosterone and androstenedione intracellularly, but only beard cells producing 5 alpha-dihydrotestosterone, in line with the scanty beard growth found in 5 alpha-reductase deficiency. Elsewhere we have shown that cultured dermal papilla cells produce extracellular matrix components and mitogenic factors. These results all concur with our original hypothesis and suggest that further studies of such cells may elucidate the paradoxical effects of Androgens on human hair follicles.

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  • cultured dermal papilla cells from androgen dependent human hair follicles e g beard contain more androgen receptors than those from non balding areas of scalp
    Journal of Endocrinology, 1992
    Co-Authors: V A Randall, M J Thornto, A G Messenge

    Abstract:

    : Androgens stimulate hair growth in many areas, e.g. the beard; they also induce regression and balding on the scalp with increasing age in genetically disposed individuals. The cause(s) of this biological conundrum is unknown but age-related; androgen-potentiated changes also occur in the prostate. The mesenchyme-derived dermal papilla situated at the base of the hair follicle is thought to play an important role in regulating the growth and development of the follicular epithelium. Since Androgens probably act on the hair follicle via the dermal papilla, cultures of dermal papilla cells from human hair follicles with differing responses to Androgens in vivo have been established and their ability to bind Androgens assessed. Receptor binding was assayed by saturation analysis (0.05-10 nmol/l) using the synthetic non-metabolizable androgen, [3H]mibolerone. Shionogi 115 cells were also assayed as a positive control. Specific high-affinity low-capacity androgen receptors were identified in 12 dermal papilla primary cell lines with similar characteristics to established androgen receptors. Cells from androgen-sensitive follicles (beard, scrotum and pubis) contained higher levels of androgen receptors than those derived from relatively androgen-insensitive non-balding scalp follicles whether the receptor content was calculated in relation to cell number, protein or DNA content of the cells. These results support the hypothesis that Androgens act on hair follicles via the dermal papilla in vivo and demonstrate that dermal papilla cells exhibit an altered phenotype in culture which depends on the body site from which they were derived.(ABSTRACT TRUNCATED AT 250 WORDS)

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